Thursday, June 30, 2011

Educational Webcast and Video Podcast of a selection of presentations of the AASLD/CDC SINGLE TOPIC CONFERENCE - Chronic Viral Hepatitis - Strategies to Improve Effectiveness of Screening and Treatment

To view these presentations you must register, the process is quick. During the registration when in doubt type in "none" to proceed. Once you begin to view/hear the webcast click on "Presentation on the sidebar to view slides and data". This is worth the effort folks.

AASLD is delighted to announce the Educational Webcast and Video Podcast of a selection of presentations of the AASLD/CDC SINGLE TOPIC CONFERENCE - Chronic Viral Hepatitis - Strategies to Improve Effectiveness of Screening and Treatment that was held in Atlanta in June 2011. These expert talks can be accessed from home/office computers and even on iPod Video, iPhone or iPad.

Available literature on the effects of interferon (IFN) treatment on development and progression of hepatocellular carcinoma (HCC) in patients with chronic virus infection reports controversial results. The primary objective of this meta-analysis was to evaluate the effect of IFN on HCC risk in patients with chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection; IFN's efficacy on local tumor progression and survival of advanced HCC patients was also assessed.

By this meta-analysis, we conclude that IFN therapy is effective in reducing overall HCC risk in chronic HCV-infected patients; using it in this subpopulation seems promising, but its administration in other subpopulations still requires further exploration.

Inflammation is the normal and natural response to body injury; however, unnecessary and chronic inflammation can wreak extreme havoc on the body and promote illness. Many times chronic inflammation goes unnoticed for years but eventually may lead to serious illness including heart disease, stroke, cancer, diabetes, sleep and mood disorders, arthritis and Alzheimer’s. Due to the increase in chronic disease, the anti-inflammatory diet has gained popularity and media attention. In general, the anti-inflammatory diet is similar to the Mediterranean style of eating and is designed to reduce risk of age-related disease and improve overall health.

Dietary Factors Contributing to Inflammation

One of the largest players in the fight against chronic inflammation is excess body weight. The inflammatory state is a vicious cycle starting with infection or illness that produces inflammation, then insulin resistance followed by weight gain and more inflammation. When an individual starts to gain weight, it can become difficult to get the body out of this constant inflammatory pathway. Typically drastic nutrition and exercise changes are needed. The modern diet contributes to inflammation through a variety of body mechanisms that are not completely understood. Eating too many fried foods, processed foods, omega-6 fats, saturated fat, refined sugar and trans fats have all been linked to increased pro-inflammatory chemicals and hormones that cause cell damage.

Foods to Eat

The anti-inflammatory diet promotes well-balanced eating, but for true success it must be a lifestyle change and not a temporary fix. Due to the anti-inflammatory effects, omega-3 fatty acids such as fresh oily fish, walnuts, ground flaxseed and fortified eggs are the staples. The primary source of fat is extra virgin olive oil. Only lean meats (turkey/chicken breast meat and seafood) and vegetable proteins (soybeans, tofu, and soy milk) are allowed. Because of their high levels of antioxidants, a colorful variety of fresh fruits and vegetables are strongly encouraged along with a variety of nuts, 100% whole wheat grains, beans and legumes. Herbs and spices such as garlic, turmeric, ginger, cinnamon, red pepper, cayenne, basil, oregano, paprika and chili peppers play a key role in flavoring foods. As far as beverages, 2-4 servings of green, white and/or oolong tea are recommended and red wine is allowed in moderate amounts (1 glass daily).

Foods to Avoid

The first step in following the anti-inflammatory diet is to eliminate refined, white sugar found in most breads, white potatoes, crackers, chips and other snack foods and sugary beverages. All fast food should be avoided. Foods which are high in ‘pro-inflammatory’ fats include some margarines, all fatty meats, all processed meats, all fried foods, regular cheese, vegetable shortening and products containing partially hydrogenated vegetable oils. In order to further avoid the damaging ‘pro-inflammatory’ fats, the anti-inflammatory diet plan suggests avoiding all dairy products, unless they are the skim/fat-free/non-fat variety. Be sure to obtain calcium from other sources or supplements, if dairy products are avoided. Excess sugar and derivatives are not recommended. But artificial sweeteners are allowed.

Does it Work?

Many aspects of the diet have been associated with better health. Research has shown cultures who eat a diet high in fruits, vegetables, nuts, seeds, fatty fish and healthy oils have lower rates of chronic disease. Keep in mind that the overall pattern of eating, maintaining a healthy weight and being physically active are the three most important factors in reducing inflammation. The inclusion or elimination of certain foods and nutrients are important but improvement will be blunted if you do not look at the big picture!

On a more serious note:

Inflammation is considered the ‘silent’ killer. The problem occurs when chronic inflammation occurs inside our body and we can’t see it or feel it. This chronic inflammation does not allow for natural repair and healing caused by the damaging ‘pro-inflammatory’ (saturated and trans) fats. Being overweight or obese increases inflammation. Inflammation is a cause of many diseases, such as Rheumatoid Arthritis, Diverticulosis, Crohn’s disease, some kidney diseases, chronic skin problems, and many forms of cardiovascular disease.

The most popular lab test used to confirm inflammation is the C-reactive protein test (CRP), although, the CRP test can’t diagnose where in the body, or why the inflammation is occurring.

Preventing inflammation

The first step is to maintain a normal body weight and get enough sleep. Skimping on sleep can increase the level of stress hormones and CRP in our blood. Frequent exercise and smoking cessation also help, as does practicing stress reduction techniques, such as prayer or mediation.

As part of a healthy diet, eat the following each week (not necessarily daily) to assist in lowering chronic inflammation:

If you would like to schedule a nutrition consult, contact Brooke at http://www.nutritionauthority.com/ or call 253-227-8284. Let a ‘Registered Dietitian’ help you clear up any nutrition confusion you may have. Brooke can personalize a ‘nutrition lifestyle plan’ to meet your specific needs. Most insurance is accepted.

Surveillance is widely accepted in clinical practice in patients who are at increased risk of developing hepatocellular carcinoma (HCC), including those with chronic hepatitis B virus (HBV) infection. Surveillance in patients with HBV infection has been recommended on the basis of findings from one randomised controlled trial from China showing a survival benefit,1 and other non-randomised or observational studies showing that surveillance detects earlier disease and improves survival. The most recent update of practice guidelines from the American Association for the Study of Liver Diseases (AASLD) recommends surveillance for HCC in Asian male hepatitis B carriers older than 40 years, Asian female hepatitis B carriers older than 50 years, hepatitis B carriers with a family history of HCC, African and North American black patients with hepatitis B, and hepatitis B carriers with cirrhosis.2

One of the main elements of surveillance is to establish what level of risk for HCC should lead to initiation of surveillance. In this issue of The Lancet Oncology, Hwai-I Yang and colleagues3 report the development and validation of a predictive score for the risk of development of HCC in patients with chronic hepatitis B. Although other groups, such as Yuen and colleagues,4 have reported risk scores for the development of this disease, this is the first group to provide validation of their risk score. The study analysed data from 3584 patients from a community-based Taiwanese cohort who were not receiving antiviral therapy and did not have cirrhosis, and validated their risk score in hospital-based cohorts from Hong Kong and South Korea.3 Variables associated with an increased risk of HCC included patient factors (male sex, increasing age), disease factors (raised concentrations of serum alanine aminotransferase), and virological factors (HBeAg positivity and increased levels of serum HBV DNA). The risk score accurately estimated the risk of development of HCC at 3, 5, and 10 years. The investigators have contributed to the evolving work into risk scores for HCC by providing validation in a large, independent multicentre cohort. They conclude that this score could allow evidenced-based decisions for clinical management of hepatitis B carriers at variable risk of HCC.

The key question for clinicians is whether or not this risk score can lead to tailored decisions in the management of patients with chronic hepatitis B, such as no surveillance in patients with a low score or a change to more frequent surveillance or use of more sensitive imaging techniques in those with a high score. Prospective studies of surveillance every 3—4 months versus 6 months, or use of CT or MRI rather than ultrasound in high-risk patients with chronic hepatitis B would be needed before a clinician could with confidence change from the standard recommendation of ultrasonography every 6 months, usually with α-fetoprotein.2 The population that was the basis of the Yang and colleagues’ risk score did not include patients with cirrhosis, which is known to be the major risk factor for HCC and is present in up to three-quarters of HBV-related HCC.5 Moreover, cirrhosis was the most important independent risk score for development of HCC in Yuen and colleagues’ risk score.4

Many Asian—American patients who are undergoing antiviral therapy have undetectable HBV DNA, normal alanine aminotransferase concentrations, and are HBeAg negative; they would have a low risk score but yet fit the criteria for surveillance recommended in the AASLD guidelines on the basis of their age or other factors (eg, presence of cirrhosis or a family history of HCC). How to resolve the different advice provided by a risk score versus a society guideline is a dilemma for the clinician. Risk scores might be most helpful in identification of patients with a very low risk of HCC who do not need surveillance, rather than leading to a change in surveillance practices in patients with a high score. Additionally, the incidence of HCC differs according to the geographical distribution of risk factors, and surveillance strategies derived from a Taiwanese or Asian populations might not apply globally. Finally, scoring systems should include known risk factors such as the presence of cirrhosis, use of alcohol, and family history of HCC, and should be validated in white and African patients who are often infected in adulthood and whose risks for HCC differ substantially from those in Asian patients with chronic HBV infection dating from birth or early childhood. Thus, risk scores for the development of HCC are in the preliminary stages of development and not yet ready for widespread use in practice.I have no conflicts of interest.

Patients with nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis may have fewer liver-related complications and less hepatocellular cancer than patients with hepatitis C virus infection, but may have similar overall mortality, according to a study published online June 17 in Hepatology.

THURSDAY, June 30 (HealthDay News) -- Patients with nonalcoholic fatty liver disease (NAFLD) with advanced fibrosis or cirrhosis may have fewer liver-related complications and less hepatocellular cancer than patients with hepatitis C virus (HCV) infection, but may have similar overall mortality, according to a study published online June 17 in Hepatology.

Neeraj Bhala, M.B.Ch.B., M.R.C.P., from the University of Oxford in the United Kingdom, and colleagues examined the long-term morbidity and mortality of patients with NAFLD with advanced fibrosis or cirrhosis. A cohort of 247 patients with NAFLD, followed up for an average of 85.6 months, and a second cohort of 264 patients with HCV infection, who were either naive or non-responders to treatment, and who were followed up for 74.9 months, were included in the study. Both cohorts were Child-Pugh class A, with liver biopsy-confirmed advanced fibrosis or cirrhosis.

The investigators found that there were 19.4 percent liver-related complications and 13.4 percent deaths or liver transplants in the NAFLD cohort. There were 16.7 percent liver-related complications and 9.4 percent deaths or liver transplants in the HCV cohort. The NAFLD cohort had significantly lower incidence of liver-related complications, including incident hepatocellular cancer, than the HCV cohort, after adjusting for age and gender. Both cohorts had similar incidence rates of cardiovascular events and overall mortality.
"Patients with NAFLD with advanced fibrosis or cirrhosis have lower rates of liver-related complications and hepatocellular cancer than corresponding patients with HCV infection, but similar overall mortality," the authors write.

Canada's federal and provincial governments are now taking more than two and a half years, on average, to approve new prescription medicines, says a new report.

The federal regulator, Health Canada, takes an average of nearly 16 months to approve new drugs as safe and effective, after which the provincial governments typically spend another 15 months or more to decide whether new drugs will be eligible for public reimbursement under their drug plans, says the report, from free-market think tank The Fraser Institute.

This combination of federal and provincial decision-making creates delays or, more often, deprives patients of access to new medicines, it claims.

The Institute's research found that only 23% of new drugs approved as safe and effective by Health Canada in 2004 had been approved for either full or partial reimbursement under provincial drug plans as of June 9, 2011, compared to 98% that had been covered by at least one private insurer.

Moreover, Health Canada took longer to certify new drugs during 2006-2009 than the European Medicines Agency (EMA) and, during five of the last six years studied (2004-2009), its performance was worse than that of the US Food and Drug Administration (FDA).

The report's authors suggest two specific policy changes to make new medicines available more quickly to Canadians. First, they say, Canada could speed up its regulatory processes by taking advantage of the knowledge and capacity of other jurisdictions, rather than attempting to duplicate the processes of the US FDA. If Canada entered into agreements of "mutual recognition" with other countries, new medications already approved in those jurisdictions could be introduced onto the Canadian market far more rapidly, and vice versa, they add.

Second, government drug programmes could be replaced with means-tested subsidised access to private insurance, they suggest. A properly-regulated and competitive private-sector insurance market, in which universal access to catastrophic drug insurance would be facilitated through means-tested subsidies for those on low incomes, could make new medicines more readily available without increasing the burden on taxpayers, the report proposes.

In fact, only a very small percentage of Canadians actually face exorbitant drug costs, says the Institute; during 1997-2002, only 3% of Canadian households spent more than 5% of their annual income on prescription drugs.

'Means-tested subsidies provided to those with low incomes, regardless of age, to purchase catastrophic drug insurance in a private, competitive insurance market benefits recipients by giving them the choice of selecting the drug plan that meets their individual medical needs and financial abilities," said Mark Rovere, study co-author and associate director of health policy studies at the Institute.

Unlike the majority of public drug plans which have small, flat co-payments, most private drug insurance plans include co-payments that are linked to the full cost of the prescription, and these encourage patients to make cost-efficient choices between alternative treatments, says the report. Consumer sensitivity to prices in turn creates incentives for physicians to prescribe treatment more efficiently and for drug manufacturers to invest efficiently in the development of new drugs, it adds.

"Allowing the private insurance market to compete through prices and service, thus eliminating government monopolies on drug prices and coverage, is the best policy choice for improving access to the newest prescription drugs," according to Mr Rovere.

Three years after the FDA linked the Heparin scandal to contaminated supplies from China, the House Energy and Commerce Committee is expanding a probe into the episode and wrote 10 drugmakers, manufacturer reps and ingredients suppliers for documents, because the agency has indicated they have info about the Chinese heparin industry and supply chains.

The move comes after the committee has twice lashed out at the FDA for failing to find those responsible for the scandal, which was linked to 81 deaths in 2007 and 2008 and traced to heparin sold by Baxter International (back story). The fatalities provoked harsh criticism of the FDA for not conducting greater oversight of foreign facilities - particularly those in China that make medicines or supply active pharmaceutical ingredients. Baxter recalled its heparin, which contained an active pharmaceutical ingredient derived from pig intestines (see photo) from hogs in rural China.

Regenerative medicine such as stem cell therapy has cast a ray of hope into many patients’ lives. Stem cell clinics, however, do not always offer patients the most effective treatments. According to a recent Naturearticle:

Many of the treatments such clinics offer — injecting a patient’s own stem cells back into his or her body in a bid to treat conditions ranging from Parkinson’s disease to spinal-cord injuries — are at best a waste of money, and at worst dangerous. “There’s real potential to damage the legitimacy of the field,” says Timothy Caulfield, who studies health law and policy at the University of Alberta in Edmonton, Canada.

The potential danger of these clinics is clear: In May, Europe’s largest stem-cell clinic was shut down after its treatments were linked to a child’s death....Please do go read the more at Scopeand the original article from Nature.

A study in this month's issue of the Journal of Hepatology identifies predictors and effects of alcohol use on liver function among young HCV-infected injection drug users in a behavioral intervention.

Hepatitis C virus (HCV) screening can provide opportunities to reduce disease progression through counseling against alcohol use, but empirical data on this issue are sparse.

Dr Steffanie Strathdee and colleagues from California determined the efficacy of a behavioral intervention in reducing alcohol use among young, HCV-infected injection drug users, and assessed whether changes in liver enzymes were associated with changes in alcohol consumption.
Both the intervention and attention-control groups were counseled to avoid alcohol use, but the intervention group received enhanced counseling.

Logistic regression, ANOVA, and continuous time Markov models were used to identify factors associated with alcohol use, changes in mean ALT and AST levels, and change in alcohol use post-intervention.
The team found that 6 months post-intervention, alcohol abstinence increased 23% in both groups, with no difference by intervention arm.

Transition from alcohol use to abstinence was associated with a decrease in liver enzymes, with a marginally greater decrease in the intervention group.

On further analysis, the team found that those who used marijuana transitioned from alcohol abstinence to consumption more rapidly than non-users.

Those who were homeless transitioned more slowly to alcohol abstinence, and those who had ever received a clinical diagnosis of liver disease transitioned more rapidly to abstinence.
Dr Strathdee's team commented, "Although, behavioral counseling to reduce alcohol consumption among HCV-infected injection drug users had a modest effect, reductions in alcohol consumption were associated with marked improvements in liver function."

"Interventions to reduce alcohol use among HCV-infected injection drug users may benefit from being integrated into clinical care and monitoring of HCV infection."J Hepatol 2011: 55(1): 45-52
30 June 2011

More Than Two-Thirds of Surveyed U.S. Clinicians Plan to Prescribe Incivek and Victrelis to Patients with Treatment-Naive Hepatitis C Virus Genotype 1Source:biowireDecision Resources, one of the world’s leading research and advisory firms for pharmaceutical and healthcare issues, finds that more than two-thirds of surveyed U.S. clinicians plan to prescribe Vertex/Johnson & Johnson/Mitsubishi Tanabe’s Incivek and Merck/Roche’s Victrelis to patients with treatment-naive hepatitis C virus genotype 1 (HCV1), and half of surveyed physicians indicate they will add Incivek or Victrelis to an HCV1 patient’s existing pegylated-interferon(peg-IFN)/ribavirin regimen. In May 2011, Incivek and Victrelis were approved as treatments for hepatitis C virus by the U.S. Food and Drug Administration. The new U.S. Physician & Payer Forum report entitled Hepatitis C Virus: How Will The Launch of Novel Antivirals Influence U.S. Physician and Payer Attitudes Towards Treatment and Reimbursement? also finds that, among the surveyed clinicians who expect to prescribe Incivek to more HCV1 treatment-naive patients than Victrelis, 64 percent cite the high sustained virologic response (SVR) rate of Incivek-based regimens as the most important factor in their prescribing decisions. Similarly, the largest proportions of managed care organizations’ (MCO) pharmacy directors who expect to add Incivek to their formularies rank SVR in nonresponders and in treatment-naive patients as the most important factors driving the inclusion of Incivek in their formularies. “Surveyed physicians estimate that an Incivek-based regimen will be used to treat more than half of all HCV1 patients and will be used in 44 percent of HCV2/3 nonresponders,” said Decision Resources Analyst LaTese Briggs, Ph.D. “Additionally, only 11 percent of surveyed clinicians expect to prescribe Victrelis over Incivek—of this small minority, 45 percent cite the possibility of a shorter treatment duration in HCV1 nonresponders along with acceptable SVR rates as the most influential factors in their decision to prescribe Victrelis over Incivek.” The report also finds that while clinicians plan to use Incivek in more than half of HCV1 treatment-naive patients, less than half of surveyed MCOs plan to reimburse Incivek-based therapy in this subpopulation. Among surveyed pharmacy directors who expect to cover Incivek, only 47 percent plan to reimburse this agent for HCV1 treatment-naive patients. According to 68 percent of surveyed MCOs, Incivek will more likely be reimbursed for treatment of HCV1 nonresponders. Similar to Incivek, more than three-quarters of surveyed MCOs who expect to cover Victrelis, plan to reimburse it for HCV1 nonresponders, but only 39 percent expect to provide reimbursement for Victrelis in HCV1 treatment-naive patients. About Decision ResourcesDecision Resources ( document.write('www.decisionresources.com'); www.decisionresources.com) is a world leader in market research publications, advisory services and consulting designed to help clients shape strategy, allocate resources and master their chosen markets. Decision Resources is a Decision Resources, Inc. company.

Wednesday, June 29, 2011

Posted by Abigail Place • June 24th, 2011

The latest article in our Clinical Practice series, Chronic Hepatitis C Infection, (see below) reviews the evaluation and initial management of chronic hepatitis C infection, with particular attention to the use of new directly acting antiviral agents in treatment regimens.

Infection with HCV affects an estimated 180 million people globally. It is a leading cause of chronic hepatitis, cirrhosis, and liver cancer and a primary indication for liver transplantation in the Western world.

Clinical Pearls•What are the predominant risk factors for hepatitis C virus infection?
The predominant risk factor for HCV acquisition is injection-drug use; among U.S. adults 20 to 59 years of age with any history of illicit injection-drug use, the prevalence of HCV infection is greater than 45%. Other risk factors include blood transfusion before 1992, high lifetime number of sexual partners, and iatrogenic transmission, including through dialysis; in large series, 15 to 30% of patients report no risk factors.

•Approximately what percentage of patients with chronic hepatitis C virus infection have progression to cirrhosis?
Although the natural history of HCV infection is highly variable, an estimated 15 to 30% of patients in whom chronic infection develops have progression to cirrhosis over the ensuing three decades. A number of factors, including a longer duration of infection, an older age at the time of exposure, male sex, coinfection with other viruses such as HIV, and daily alcohol consumption, but not viral level or genotype, have been consistently associated with an increased risk of fibrosis.

Table 1. Predictors of a Favorable Response to Treatment with Peginterferon and Ribavirin.

Morning Report QuestionsQ: What methods can be used to quantify hepatic fibrosis?A: Several methods have been used to quantify hepatic fibrosis, including the simple aspartate aminotransferase:platelet ratio index and commercially available assays of some or most of the following biomarkers: (alpha)2-macroglobulin, (alpha)2-globulin, (gamma)-globulin, apolipoprotein A-I, (gamma)-glutamyltransferase, total bilirubin, and hyaluronic acid.

Q:What treatment is the standard of care for all HCV genotypes?A: Over the past decade, on the basis of considerable data from randomized trials, pegylated interferon (peginterferon) plus ribavirin became the standard of care for all HCV genotypes. Regardless of the infecting genotype, the likelihood of a sustained virologic response is lower among patients with a high pretreatment HCV RNA level and higher among patients with better adherence to antiviral therapy.

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations.

A 45-year-old man undergoing a routine examination for life insurance is noted to have an aspartate aminotransferase level of 80 U per milliliter (normal range, 9 to 40) and an alanine aminotransferase level of 110 U per milliliter (normal range, 7 to 52). He reports a remote history of intravenous drug use. Tests for hepatitis C antibody and hepatitis B surface antibody are positive, and tests for hepatitis A and human immunodeficiency virus (HIV) antibodies are negative. Genotyping of the hepatitis C virus (HCV) reveals genotype 1b; the viral load is 2,460,000 IU per milliliter. The complete blood count is normal; the platelet count is 220×109 per liter. An abdominal ultrasonogram is normal. How should this patient's case be managed?

The Clinical Problem

Infection with HCV affects an estimated 180 million people globally. It is a leading cause of chronic hepatitis, cirrhosis, and liver cancer and a primary indication for liver transplantation in the Western world.1 There are at least six major HCV genotypes whose prevalence varies geographically. Genotype 1 accounts for the majority of infections in North America, South America, and Europe.2The predominant risk factor for HCV acquisition is injection-drug use; among U.S. adults 20 to 59 years of age with any history of illicit injection-drug use, the prevalence of HCV infection is greater than 45%.3 Other risk factors include blood transfusion before 1992, high lifetime number of sexual partners, and iatrogenic transmission, including through dialysis4,5,; in large series, 15 to 30% of patients report no risk factors.

The host immune response largely determines whether HCV is eradicated spontaneously or persists (as it does in the majority of patients).6Although the natural history of HCV infection is highly variable, an estimated 15 to 30% of patients in whom chronic infection develops have progression to cirrhosis over the ensuing three decades.7 A number of factors, but not viral level or genotype, have been consistently associated with an increased risk of fibrosis

Histologic Features of HCV Infection, According to Different Scoring Systems.), there is widespread agreement that antiviral therapy is indicated because of the high risk of cirrhosis.2,12
Prospective data indicate that the stage of fibrosis predicts clinical outcomes; the cumulative 6-year incidence of liver transplantation or liver-related death ranges from 4% for an Ishak fibrosis score of 2 to 28% for an Ishak score of 6.11 Because of the extended interval between infection and the emergence of complications, the HCV-related disease burden is projected to increase severalfold over the next 20 years.13

The hepatitis C virus, an enveloped flavivirus, was first cloned in 198914; the positive-stranded viral RNA (with approximately 9600 nucleotides) encodes a polyprotein precursor of approximately 3000 amino acids

The coordinated activities of CD4+ T cells and cytotoxic CD8+ T cells, primed in the context of HLA class II and I alleles, respectively, on antigen-presenting cells, are critically important for the control of acute HCV infection. Mutations in viral epitopes that are targeted by cytotoxic CD8+ T cells can allow the virus to escape immune-mediated clearance. Up-regulation of inhibitory receptors on exhausted (functionally impaired) T cells is another mechanism of T-cell dysfunction during chronic infection (Figure 3C).17,18

Strategies and Evidence

Diagnosis and Clinical Staging

Liver biopsy remains the standard for assessment of hepatic fibrosis and is helpful for prognostication and decision making. The histologic pattern of HCV infection consists of lymphocyte infiltration of the parenchyma, lymphoid follicles in portal areas, and reactive bile-duct changes. However, liver biopsy is costly and invasive, and it carries a risk of complications (e.g., 1 to 5% of patients who undergo the procedure require hospitalization).19 Additional limitations of biopsy include sampling error and interobserver variability.

Several methods have been used to quantify hepatic fibrosis, including the simple aspartate aminotransferase:platelet ratio index (APRI) and commercially available assays of some or most of the following biomarkers: α2-macroglobulin, α2-globulin, γ-globulin, apolipoprotein A-I, γ-glutamyltransferase, total bilirubin, and hyaluronic acid.19-21 (For more information on APRI, see Table 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org.) The sensitivity and specificity of these assays for the detection of clinically significant fibrosis range from 41 to 94% and from 44 to 95%, respectively,21,22 and the assays are typically much better at detecting advanced fibrosis and cirrhosis than mild-to-moderate fibrosis. Combining assays (e.g., APRI and FibroSURE or HepaScore) appears to increase the diagnostic accuracy and may eliminate the need for liver biopsy in more than half of patients.12,22,23 Optimal cutoff values for establishing the accurate diagnosis of fibrosis may vary across populations, depending in part on the prevalence of advanced fibrosis.23

Management

Interferon-Based Antiviral Therapy

Substantial progress has been made in the treatment of HCV infection. The goals of therapy are to prevent complications and death from HCV infection; regardless of the stage of fibrosis, symptomatic extrahepatic HCV (e.g., cryoglobulinemia) is an indication for therapy.2 Over the past decade, on the basis of considerable data from randomized trials, pegylated interferon (peginterferon) plus ribavirin became the standard of care for all HCV genotypes.24-26

The two licensed peginterferons (Pegasys, Roche, and PegIntron, Merck) have been shown in head-to-head comparison to be equivalent in efficacy and to have similar safety profiles.27 Among patients with genotype 1 who are treated with peginterferon at the standard weight-based dose of ribavirin (1000 or 1200 mg per day) for 48 weeks, 40 to 50% have a sustained virologic response (defined as an undetectable HCV RNA level 24 weeks after the cessation of antiviral therapy). A shorter course of treatment and a lower ribavirin dose are associated with lower rates of sustained virologic response (and higher relapse rates) among genotype 1–infected patients.24-26 In contrast, patients with genotype 2 or 3, who account for approximately one quarter of HCV-infected patients in the United States, have rates of sustained virologic response in the range of 70 to 80% after taking peginterferon and ribavirin at a reduced dose (800 mg per day) for 24 weeks.25 A sustained virologic response is associated with permanent cure in the vast majority of patients.

Predictors of a Favorable Response to Treatment with Peginterferon and Ribavirin. shows virus-specific and patient-specific factors that affect the likelihood of a sustained virologic response.2,24-26,28-30 Regardless of the infecting genotype, the likelihood of a sustained virologic response is lower among patients with a high pretreatment HCV RNA level (with a high level defined as >600,000 IU per milliliter in some studies and >800,000 IU per milliliter in others) and higher among patients with better adherence to antiviral therapy (receiving 80% of total interferon and ribavirin doses for 80% of the expected duration of therapy). Adherence can be problematic because of the plethora of side effects, including fevers, influenza-like symptoms, headache, cytopenias, fatigue, anorexia, depression, and anxiety.31

On-treatment viral kinetics have emerged as important predictors of the likelihood of response and are used to guide the duration of therapy.2 An early virologic response is defined as a decrease in the HCV RNA level of at least 2 log10 IU per milliliter or the complete absence of serum HCV RNA at week 12 of therapy.2 The lack of such a response in a patient has a very high negative predictive value for a sustained virologic response. Among patients with previously untreated genotype 1 infection, more than 97% of those who do not have an early virologic response to treatment will not have a sustained response. A rapid virologic response, defined as an undetectable HCV RNA level (<50 IU per milliliter) at week 4 of treatment, has been shown to predict a sustained virologic response, as well as to identify those patients for whom the duration of therapy can be shortened without compromising the virologic response. A recent meta-analysis of seven randomized trials has shown that genotype 1–infected patients with a low baseline HCV RNA level (<400,000 IU per milliliter) who have a rapid virologic response may discontinue therapy at 24 weeks rather than continue for the standard 48 weeks.32 A reduction of the treatment duration has the added benefits of decreased costs and side effects.2,32

Race is another important predictor of response to antiviral therapy. Black patients have significantly lower rates of sustained virologic response than white patients (28% vs. 52%).33 Although the reasons for this difference have been uncertain, recent data from genomewide association studies have indicated that single-nucleotide polymorphisms (SNPs) on chromosome 19 in or near the interleukin-28B gene (IL28B, encoding interferon lambda-3) are highly predictive of successful antiviral treatment.34 In an analysis that was adjusted for other predictors, the chance of cure was more than doubled with homozygosity for the C allele at the rs12979860 SNP, as compared with the TT genotype (78% for the CC genotype, 38% for the TC genotype, and 26% for the TT genotype). The C allele is much more frequent in white and Asian populations than in black populations. Moreover, in the Viral Resistance to Antiviral Therapy of Chronic Hepatitis C study (VIRAHEP-C; ClinicalTrials.gov number, NCT00038974), which involved patients infected with HCV genotype 1, pretreatment HCV-specific CD4+ T-cell responses were significantly lower in black patients than in white patients and correlated with lower rates of a sustained virologic response.35 This study also showed that the expression level of the programmed death 1 (PD-1) receptor, with higher levels reflecting greater functional impairment of HCV-specific CD8+ T cells, was inversely associated with the likelihood of a sustained virologic response.36

Directly Acting Antiviral Agents

The molecular characterization of the virologic features (Figure 3A) and life cycle of HCV has led to the development of directly acting antiviral agents, with the goal of improved efficacy and fewer adverse effects as compared with interferon-based regimens.37 All the HCV enzymes, which are essential for HCV replication, are potential targets; the nonstructural 3 (NS3) serine protease inhibitors are the furthest along in development. In addition to ablating replication, protease inhibition blocks the ability of the NS3/4A serine protease to cleave the HCV polyprotein and interferon-β promoter stimulator 1, thus restoring innate immune signaling within hepatocytes (Figure 3B).15 Two protease inhibitors, telaprevir and boceprevir, were recently approved by the Food and Drug Administration (FDA).

In the Protease Inhibition for Viral Evaluation 1 trial (PROVE1, NCT00336479)38 and PROVE2 trial (NCT00372385),39 which involved genotype 1–infected patients who had not previously received treatment, the rates of sustained virologic response were 61% and 69%, respectively, among those who received a 12-week course of telaprevir, an orally bioavailable inhibitor of NS3/4A,38 in combination with peginterferon–ribavirin, which was continued for an additional 12 weeks (total duration of antiviral therapy, 24 weeks; T12PR24 in (Figure 4)

Figure 4

Study Design and Results of Five Published Trials of a Combination of a Protease Inhibitor and Peginterferon–Ribavirin in Patients with Chronic HCV Infection Who Had Not Previously Received Treatment.). As compared with standard therapy with peginterferon–ribavirin, the addition of telaprevir resulted in a shorter median time to achieve an undetectable HCV RNA level (<30 days, vs. 113 days).39 Major side effects of telaprevir included rash, pruritus, anemia, and gastrointestinal symptoms. The observation that viral relapse (detectable HCV RNA level during the 24-week posttreatment period in patients with an end-of-treatment response) occurred in 48% of patients who did not receive ribavirin (T12P12 in Figure 4) underscores the critical role of this agent in preventing relapse and the emergence of telaprevir resistance.39,43

The ADVANCE (A New Direction in HCV Care: A Study of Treatment-Naive Hepatitis C Patients with Telaprevir) trial (NCT00627926), a phase III randomized trial reported in this issue of the Journal, incorporated on-treatment response to tailor the duration of additional peginterferon–ribavirin.40 Telaprevir and peginterferon–ribavirin were administered for the first 12 weeks or for 8 weeks, followed by 4 weeks of placebo. Extended rapid virologic response was defined as an undetectable HCV RNA level (<25 IU per milliliter) at week 4 and week 12 of therapy37; patients who did not have an extended rapid virologic response received 36 additional weeks of peginterferon–ribavirin, for a total of 48 weeks. More than half of the telaprevir-treated patients had an extended rapid virologic response, and 24 weeks of total therapy was associated with a rate of sustained virologic response that was higher than 80% among these patients. As in all the other telaprevir studies, virologic failure was more common in patients with genotype 1a than in those with genotype 1b. The REALIZE (Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes) study (NCT00703118), also reported in this issue of the Journal, showed that the addition of telaprevir to peginterferon–ribavirin significantly increased the rate of sustained virologic response among patients who had previously received treatment, particularly in prior relapsers (patients with an undetectable HCV RNA level at the end of a prior course of peginterferon–ribavirin therapy but with a detectable HCV RNA level thereafter).44

The Serine Protease Inhibitor Therapy 1 trial (SPRINT-1, NCT00423670)41 and the SPRINT-2 trial (NCT00705432)42 have shown the efficacy of boceprevir in combination with peginterferon alfa-2b and ribavirin in genotype 1–infected patients who had not previously received treatment (Figure 4); another recent report in the Journal showed the efficacy of this regimen in patients who had previously received treatment.45 These trials included groups with a 4-week lead-in phase of peginterferon–ribavirin before the addition of boceprevir in order to lower viral levels, theoretically reducing the risk that drug-resistant mutations would emerge.42,45,46 SPRINT-2 used a response-guided antiviral strategy; patients whose tests for HCV RNA were negative by week 8 and remained so up to week 24 were given 24 weeks of boceprevir with peginterferon–ribavirin after the lead-in phase. Rates of sustained virologic response were 63% and 66% among patients receiving a total of 28 or 48 weeks of therapy, respectively, with higher rates among whites than among blacks. Patients in whom the HCV RNA level decreased by less than 1.0 log10 IU per milliliter during the lead-in phase had significantly higher rates of virologic failure. Principal side effects of boceprevir included anemia (necessitating treatment with erythropoietin analogues in many patients) and dysgeusia, which appeared to be more common than previously reported with telaprevir; rash was reported less frequently than in the telaprevir trials.37

Mathematical modeling has projected that if the rate of response to antiviral therapy increases to 80%, which appears to be likely in the foreseeable future,13 treatment of half of HCV-infected persons would reduce cases of cirrhosis by 15%, cases of hepatocellular carcinoma by 30%, and deaths due to liver disease by 34% after just 10 years.13

Areas of Uncertainty

Transient elastography (FibroScan, Echosens) is a novel noninvasive technique that measures liver stiffness by assessing the velocity of a shear wave created by a transitory vibration.23 Thresholds for a high likelihood of clinically significant fibrosis (Metavir score ≥2) have been defined. The technique has an increased failure rate among obese patients, and it has not been approved by the FDA. Whether modifications of existing technologies (e.g., computed tomography and magnetic resonance imaging) will provide sensitive differentiation of levels of hepatic fibrosis requires further study.

Although peginterferon–ribavirin is likely to remain the backbone of antiviral therapy for the foreseeable future, options for treating HCV are expected to expand rapidly in upcoming years. The optimal combination of agents (including nucleoside and nonnucleoside polymerase inhibitors, inhibitors of NS4B and NS5A proteases, modulators of the immune response, and medications that interfere with lipid metabolism, which is essential for the assembly and maturation of HCV particles) and duration of therapy will need to be defined, in order to maximize rates of sustained virologic response while minimizing the risk that resistance will develop.46,47 A recent pilot study of a combination of directly acting antiviral agents suggests the possibility of treating HCV infection with an interferon-free, oral approach.48 Further study is needed in subgroups of patients with lower response rates, including black patients, patients without a response to prior treatment, liver-transplant recipients, and those who have coinfection with HIV, a high baseline viral load, advanced fibrosis, or insulin resistance.

Guidelines

The American Association for the Study of Liver Diseases2 and the American Gastroenterological Association49 have published guidelines for the assessment and management of chronic HCV infection, but these guidelines were issued before the publication of data from randomized trials of directly acting antiviral agents. Newer European guidelines take these data into account50; the recommendations provided below are generally consistent with these guidelines.

Conclusions and Recommendations

The patient described in the vignette has HCV genotype 1 with a high viral load. He should be vaccinated for hepatitis A because of an increased risk of liver failure among patients with chronic hepatitis C infection; hepatitis B vaccination is also indicated in those without evidence of prior exposure.2 Possible contraindications to treatment (e.g., depression) should be determined, and the patient should be informed about potential side effects of antiviral therapy.31,37-39,41,42 Although some clinicians would administer treatment without performing a liver biopsy, I would recommend a biopsy to assess the degree of fibrosis.31 For a patient with clinically significant fibrosis (Metavir score ≥2), triple antiviral therapy with peginterferon–ribavirin and an NS3/4A protease inhibitor, either telaprevir or boceprevir, should be recommended.

On the basis of data from recent randomized trials, a reasonable initial regimen would be telaprevir with peginterferon–ribavirin for 12 weeks. If tests for HCV RNA were negative at weeks 4 through 12 (indicating an extended rapid virologic response), only 12 additional weeks of peginterferon–ribavirin would be recommended, whereas if an extended rapid virologic response were not achieved, peginterferon–ribavirin would be continued for an additional 36 weeks.37 If boceprevir were used, according to new FDA guidelines, a 4-week lead-in phase of peginterferon–ribavirin would be followed by peginterferon–ribavirin and boceprevir for 24 weeks (a total of 28 weeks) if tests for HCV RNA were negative at weeks 8 through 24 of treatment. If the tests were positive between weeks 8 and 24 but negative at week 24, peginterferon–ribavirin and boceprevir would be continued for an additional 8 weeks, followed by an additional 12 weeks of peginterferon–ribavirin (a total of 48 weeks).

Alternatively, if the patient has milder fibrosis and is reluctant to receive treatment, it would be reasonable to wait and reevaluate as new therapeutic agents become available.46,47

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

No potential conflict of interest relevant to this article was reported.

HCV Education
Review learning activities, editorials, with new data about interferon-free regimens approved for HCV, as well as investigational drugs still in the pipeline. Links are provided to support, patient friendly information, clinical trials, peer-reviewed journals, videos, conferences with commentary, all updated on a continuous basis.

Users can search for a hepatitis C clinical trial by category (genotype), or learn how to evaluate a clinical trial and become familiar with commonly used terms. HCV Advocate offers an easy to navigate HCV Medications Blog as well, organized by HCV genotype

View each rebuttal and all ongoing media coverage. In June the HCV community was blindsided when an article with a somewhat "clickbait" headline was released by The Guardian. The Guardian reported on a systematic review published by the Cochrane Collaboration that suggested achieving SVR (cure) for patients using hepatitis C direct-acting antivirals (DAAs) doesn't correlate with any long term benefits.

The controversy over expensive new drugs for hepatitis C
Link to research and news articles addressing the high cost of hepatitis C drugs; insurance restrictions - private insurers/Medicaid - and availability of generic versions/India, Egypt and other lower-income countries or through online "buyers clubs"

Liver Cancer After Treatment For Hepatitis C
​Research demonstrates that while SVR markedly reduced liver-related complications and liver cancer, some long-term risk for liver cancer remained in those who were cured of Hepatitis C. But after direct-acting antiviral therapy does the risk of developing liver cancer increase?

Meeting Updates

April 19-23
The European Association for the Study of the Liver (EASL) International Liver Congress (ILC 2017)

Merck today announced its strategic decision to discontinue the development of the investigational combination regimens MK-3682B (grazoprevir/ruzasvir/ uprifosbuvir) and MK-3682C (ruzasvir/uprifosbuvir) for the treatment of chronic hepatitis C virus (HCV) infection. This decision was made based on a review of available Phase 2 efficacy data and in consideration of the evolving marketplace and the growing number of treatment options available for patients with chronic HCV infection

Two HCV Drugs to Be Discontinued
The Food and Drug Administration (FDA) announced that Rebetol(ribavirin; Merck) capsules and PegIntron (peginterferon alfa-2b; Merck) for Injection are being discontinued. The decision is business-related and not due to safety or efficacy issues with the drugs.

Rebetol is a nucleoside analogue indicated for chronic hepatitis C in combination with interferon alfa-2b (pegylated and nonpegylated), in patients ≥3 years of age with compensated liver disease. It is supplied as 200mg capsules in 56-, 70-, and 84-count bottles. The Rebetol discontinuation is effective February 1, 2016.
PegIntron is an antiviral indicated for treatment of chronic hepatitis C in patients with compensated liver disease. It is supplied as 50mcg/0.5mL, 80mcg/0.5mL, 120mcg/0.5mL, and 150mcg/0.5mL single-use vials and single-use pre-filled pens. No effective date is available for the PegIntron discontinuation.

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